Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil

ABSTRACT

or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for dementiacombining a pyrazoloquinoline derivative having phosphodiesterase 9(PDE9) inhibitory action or a pharmaceutically acceptable salt thereof,and donepezil or a pharmaceutically acceptable salt thereof.

BACKGROUND ART

Pyrazoloquinoline derivatives represented by formula (I) (hereunderreferred to as “compound (I)”) have phosphodiesterase 9 (PDE9)inhibitory action, and are considered to have promising ameliorativeeffects on cognitive function in Alzheimer's disease (PTL 1).

Donepezil, represented by formula (II) (hereunder referred to as“compound (II)”) has acetylcholine esterase-inhibitory action, and hasbeen reported to exhibit an effect against Alzheimer's disease and Lewybody dementia (see NPLs 1, 2 and 3).

In addition, the acetylcholine esterase inhibitors galantamine andrivastigmine and the NMDA receptor antagonist memantine have beenapproved as therapeutic agents for Alzheimer's disease. Donepezil isindicated for mild to severe Alzheimer's disease, and has been reportedto have, in addition to a cognitive function-ameliorating effect, alsoan effect against peripheral symptoms such as agitation, anxiety,apathy, delusion, depression, disinhibition, hallucination,irritability, aberrant motor behavior and apathy (BPSD: Behavioral andPsychological Symptoms of Dementia) (see NPLs 4 and 5). Galantamine andrivastigmine are indicated for mild to moderate Alzheimer's disease (seeNPLs 6 and 7). Memantine has been reported to have efficacy forameliorating cognitive function, and for BPSD (agitation, irritability,aggression and behavioral disorder) in moderate to severe Alzheimer'sdisease (see NPLs 8 and 9). Combined use of different acetylcholineesterase inhibitors is contraindicated, but any acetylcholine esteraseinhibitor may be used in combination with memantine. According to the2010 Dementia Disease Treatment Guidelines, acetylcholine esteraseinhibitors are recommended for the core symptoms of Alzheimer's disease,with one of donepezil, galantamine or rivastigmine being selected first,and then switching to another acetylcholine esterase inhibitor if aproblem arises in terms of effect or tolerance. When the effect of theacetylcholine esterase inhibitor is inadequate or a problem arises interms of tolerance, combination with memantine or switching to memantinemay be considered.

Acetylcholine esterase inhibitors, however, have been reported to havedigestive system side-effects, and to aggravate Parkinson's symptoms(see NPL 10). In cases where acetylcholine esterase inhibitors cannot beused due to side-effects or tolerance, memantine may be selected if thepatient has moderate to severe Alzheimer's disease, but at the currenttime no effective method of treatment exists for other patients. Thecombined use of acetylcholine esterase inhibitors with memantine ispossible in patients that experience inadequate effects, but opinionsare divided since some reports have indicated an effect by theircombined use (see NPL 11) while other reports have indicated no effect(see NPL 12).

CITATION LIST Patent Literature

[PTL 1] U.S. Pat. No. 8,563,565

Non-Patent Literature

-   [NPL 1] Homma et al., Dement. Geriatr. Cogn. Disord., 2000, vol.    11, p. 299-   [NPL 2] Homma et al., Dement. Geriatr. Cogn. Disord., 2008, vol.    25, p. 399-   [NPL 3] Mori et al., Ann. Neurol, vol. 72, p. 41 2012-   [NPL 4] Holmes at al., Neurology, 2004, vol. 63, p. 214-   [NPL 5] Gauthier et al., Int Psychogeriatr, 2002, vol. 14, p. 389-   [NPL 6] Raskind et al., Neurology, 2000, vol. 54, p. 226-   [NPL 7] Winblad et al., Neurology, 2007, vol. 69, p.S14-   [NPL 8] Mecocci et al., Int J Geriatr Psychiatry, vol. 24, p. 532-   [NPL 9] Grossberg et al., Dement Geriatr Cogn Disord, 2009, vol.    27, p. 164-   [NPL 10] Bourke et al., Ann. Pharmacother., 1998, vol. 32, p. 610-   [NPL 11] Lopez et al., J Neurol Neurosurg Psychiatry, 2009, vol.    80, p. 600-   [NPL 12] Howard et al., New Eng J. Med., 2012, vol. 366, p. 893

SUMMARY OF INVENTION Technical Problem

It is currently the case that no satisfactory method of treatment existsfor Alzheimer's disease or Lewy body dementia, while an effectiveanti-dementia agent is also yet to be developed.

Solution to Problem

In order to solve this problem, the present inventors have carried outmuch ardent research using a scopolamine-induced cognitive impairmentrat model, and as a result we have completed this invention upon findingthat the combined use of compound (I) or a pharmaceutically acceptablesalt thereof with compound (II) or a pharmaceutically acceptable saltthereof surprisingly exhibits an effect of inhibitingscopolamine-induced cognitive impairment, in doses that are ineffectivewith each alone.

Specifically, the invention relates to the following <1> to <19.3>.

<1> A therapeutic agent for Alzheimer's disease or Lewy body dementia,for combined use of(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof.<2> The therapeutic agent according to <1>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<3> The therapeutic agent according to <1> or <2>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<4> The therapeutic agent according to any one of <1> to <3>, whereinthe Alzheimer's disease is mild, moderate or severe Alzheimer's disease.<5> A therapeutic agent for Alzheimer's disease or Lewy body dementiafor simultaneous or separate administration of(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof.<6> The therapeutic agent according to <5>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<7> The therapeutic agent according to <5> or <6>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<8> The therapeutic agent according to any one of <5> to <7>, whereinthe Alzheimer's disease is mild, moderate or severe Alzheimer's disease.<9> A therapeutic agent for Alzheimer's disease or Lewy body dementia,comprising(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof.<10> The therapeutic agent according to <9>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<11> The therapeutic agent according to <9> or <10>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<12> The therapeutic agent according to any one of <9> to <11>, whereinthe Alzheimer's disease is mild, moderate or severe Alzheimer's disease.<13> Donepezil represented by formula (II):

or a pharmaceutically acceptable salt thereof, for treatment ofAlzheimer's disease or Lewy body dementia by use in combination with(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof.<13.1> Donepezil or a pharmaceutically acceptable salt thereof accordingto <13>, wherein the donepezil or pharmaceutically acceptable saltthereof is donepezil hydrochloride.<13.2> Donepezil or a pharmaceutically acceptable salt thereof accordingto <13> or <13.1>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<13.3> Donepezil or a pharmaceutically acceptable salt thereof accordingto any one of <13> to <13.2>, wherein the Alzheimer's disease is mild,moderate or severe Alzheimer's disease.<14>(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, for treatment ofAlzheimer's disease or Lewy body dementia by use in combination withdonepezil represented by formula (II):

or a pharmaceutically acceptable salt thereof.<14.1> A compound represented by formula (I) or a pharmaceuticallyacceptable salt thereof according to <14>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<14.2> A compound represented by formula (I) or a pharmaceuticallyacceptable salt thereof according to <14> or <14.1>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<14.3> A compound represented by formula (I) or a pharmaceuticallyacceptable salt thereof according to any one of <14> to <14.2>, whereinthe Alzheimer's disease is mild, moderate or severe Alzheimer's disease.<15> A method for treating Alzheimer's disease or Lewy body dementia forcombined use of(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof.<15.1> The method according to <15>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<15.2> The method according to <15> or <15.1>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<15.3> The method according to any one of <15> to <15.2>, wherein theAlzheimer's disease is mild, moderate or severe Alzheimer's disease.<16> A pharmaceutical composition comprising(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, donepezil represented byformula (II):

or a pharmaceutically acceptable salt thereof, and an excipient.<16.1> The pharmaceutical composition according to <16>, wherein thedonepezil or pharmaceutically acceptable salt thereof is donepezilhydrochloride.<16.2> The pharmaceutical composition according to <16> or <16.1>,wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<17> A kit comprising:

a pharmaceutical composition comprising(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and an excipient, and

a pharmaceutical composition comprising donepezil represented by formula(II):

or a pharmaceutically acceptable salt thereof, and an excipient.<17.1> The kit according to <17>, wherein the donepezil orpharmaceutically acceptable salt thereof is donepezil hydrochloride.<17.2> The kit according to <17> or <17.1>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<18> The use of donepezil represented by formula (II):

or a pharmaceutically acceptable salt thereof, for production of atherapeutic agent for Alzheimer's disease or Lewy body dementia by usein combination with(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof.<18.1> The use of donepezil or a pharmaceutically acceptable saltthereof according to <18>, wherein the donepezil or pharmaceuticallyacceptable salt thereof is donepezil hydrochloride.<18.2> The use of donepezil or a pharmaceutically acceptable saltthereof according to <18> or <18.1>, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<18.3> The use of donepezil or a pharmaceutically acceptable saltthereof according to any one of <18> to <18.2>, wherein the Alzheimer'sdisease is mild, moderate or severe Alzheimer's disease.<19> The use of(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, for production of atherapeutic agent for Alzheimer's disease or Lewy body dementia by usein combination with donepezil represented by formula (II):

or a pharmaceutically acceptable salt thereof.<19.1> The use of a compound represented by formula (I) or apharmaceutically acceptable salt thereof according to <19>, wherein thedonepezil or pharmaceutically acceptable salt thereof is donepezilhydrochloride.<19.2> The use of a compound represented by formula (I) or apharmaceutically acceptable salt thereof according to <19> or <19.1>,wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.<19.3> The use of a compound represented by formula (I) or apharmaceutically acceptable salt thereof according to any one of <19> to<19.2>, wherein the Alzheimer's disease is mild, moderate or severeAlzheimer's disease.

Advantageous Effects of Invention

The present invention provides a therapeutic agent for Alzheimer'sdisease and Lewy body dementia, combining a pyrazoloquinoline derivativerepresented by formula (I) having PDE9 inhibitory action, or apharmaceutically acceptable salt thereof, and donepezil havingacetylcholine esterase inhibitory action, or a pharmaceuticallyacceptable salt thereof. The therapeutic agent using this combinationexhibits a more notable ameliorative effect on cognitive function inanimal models compared to their uses alone, and it has potential for useas a therapeutic agent for Alzheimer's disease and Lewy body dementia.

DESCRIPTION OF EMBODIMENTS

The present invention will now be explained in detail.

A “pharmaceutically acceptable salt” as referred to throughout thepresent specification is not particularly limited as long as it is asalt formed with the compound of the invention, and specific examplesinclude acid addition salts such as inorganic acid salts, organic acidsalts or acidic amino acid salts.

Unless otherwise specified, in the context of “pharmaceuticallyacceptable salt” as used herein, the number of acid molecules per onemolecule of the compound in a formed salt is not particularly limited aslong as the salt is formed in an appropriate ratio. In one embodiment,the number of acid molecules per one molecule of the compound is about0.1 to about 5; in another embodiment, the number of acid molecules perone molecule of the compound is about 0.5 to about 2; and in stillanother embodiment, the number of acid molecules per one molecule of thecompound is about 0.5, about 1 or about 2.

Specific examples of an inorganic acid salt include hydrochloride,hydrobromide, sulfate, nitrate and phosphate, and specific examples ofan organic acid salt include acetate, succinate, fumarate, maleate,tartrate, citrate, lactate, stearate, benzoate, methanesulfonate,p-toluenesulfonate and benzenesulfonate.

Specific examples of an acidic amino acid salt include aspartate andglutamate.

[Formulation]

The pharmaceutical composition of the invention can be produced bymixing a pharmaceutically acceptable additive with compound (I) or apharmaceutically acceptable salt thereof, and/or compound (II) or apharmaceutically acceptable salt thereof. The pharmaceutical compositionof the invention can be produced by a known method, such as the methoddescribed in the General Rules for Preparations of the JapanesePharmacopoeia, 16th Edition.

The pharmaceutical composition of the invention can be appropriatelyadministered to a patient according to the dosage form.

The dose of compound (I) or a pharmaceutically acceptable salt thereofand compound (II) or a pharmaceutically acceptable salt thereofaccording to the invention will vary depending on the severity ofsymptoms, the patient age, gender and body weight, the form ofadministration and type of salt, and the specific type of disease, andthe like; but usually, in adult, about 30 μg to 10 g, in one embodiment100 μg to 5 g, and in another embodiment 100 μg to 1 g is administeredorally per day, in a single dose or in several divided doses; or about30 μg to 1 g, in one embodiment 100 μg to 500 mg, and in anotherembodiment 100 μg to 300 mg is administered by injection per day, in asingle dose or in several divided doses.

EXAMPLES

Compound (I) can be produced by the method described in PTL 1, forexample.

Pharmacological Test Examples

The present inventors confirmed the combined effects of compound (I) anddonepezil hydrochloride using the following animal model.

[Test Example 1] Novel Object Recognition Test Using Rats withScopolamine-Induced Cognitive Impairment

Acetylcholine nervous system disorder has been reported in Alzheimer'sdisease and Lewy body dementia (Whitehouse et al., Science, 1982, vol.215, p. 1237, Shimada et al., Neurology, vol. 73, p. 273, 2009,Tiraboschi et al., Neurology 54 (2000) 407-411, Peny et. al.,NeuroReport, vol. 5, pp. 747-749 (1994)), and scopolamine-administeredanimals are utilizable as an animal model for Alzheimer's disease andLewy body dementia.

Scopolamine is a muscarine receptor inhibitor which blocks acetylcholinenervous system transmission. The acetylcholine nervous system isinvolved in memory and attention, and healthy humans or animalsadministered scopolamine exhibit dementia-like amnesia symptoms whichare attenuated by drugs used for treatment of cognitive impairment inAlzheimer's disease and Lewy body dementia (Snyder et al., Alzheimer's &Dementia 1 (2005) 126-135, Sambeth et al., European Journal ofPharmacology, vol. 572 (2007) pp. 151-159).

Materials and Methods

6-week-old male Long Evans rats (Institute for Animal Reproduction) weresubjected to the test. A habituation process to the experimentalprocedure was carried out once per day for 2 days prior to the test. Inthe habituation process, a vehicle was administered to the rats, andthen the rats were placed in an empty test apparatus (40 cm×30 cm×45 cmheight) and allowed to explore for 3 minutes, and after then placed in awaiting chamber (13 cm×30 cm×45 cm height) for about 1 minute, they werereturned to the empty test apparatus again and left for 5 minutes.

An acquisition trial (T1) was carried out on the day of the test.Compound (I) was orally administered 2 hours before T1. Donepezilhydrochloride was orally administered 1 hour before T1. Scopolamine(Wako Pure Chemical Industries, Ltd.) was subcutaneously administered 30minutes before T1 at a dose of 0.7 mg/kg. In T1, the rats werehabituated to the empty test apparatus for 3 minutes and then placed inthe waiting chamber. After setting two identical objects in the testapparatus, the rats were returned into the test apparatus again andallowed to freely explore the two identical objects for 5 minutes. Therats were then returned into their rearing cages. After 2 hours, aretention trial (T2) was carried out. The rats were placed in the emptytest apparatus for 3 minutes for habituation, and were then transferredinto the waiting chamber. After setting an object used in T1 (“familiar”object) and an object not used in T1 (“novel” object) in the testapparatus, the rats were again returned into the test apparatus andallowed to freely explore these objects for 3 minutes. The objects werewiped with a wet wipe impregnated with ethanol after each experiment soas to leave no trace of odor. The behaviors of the rats during T1 and T2were recorded by a digital video camera, and the total exploration timefor each object was manually measured using a stopwatch. Exploratorybehavior was defined as the behavior in which the rat brings its nosewithin 2 cm of the object and directs its nose toward the object.

In the novel object recognition test, the percentage of exploration ofthe novel object in T2 is considered to be an index for amnesia,reflecting discrimination between the familiar object and the novelobject. The percentage of exploration of the novel object was calculatedby the following formula.

The percentage of exploration of the novel object (%)=N/(N+F)×100

F: time spent in exploring the familiar objectN: time spent in exploring the novel object

Rats whose total time spent in exploring the objects during T1 or T2 was10 seconds or less or rats whose percentage of the time spent inexploring either of the objects during T1 was not less than 70% or notmore than 30% of the total exploration time were excluded from the dataanalysis.

The results were expressed as mean±standard error. The differencebetween the normal control group untreated with scopolamine and thedisease control group treated with scopolamine was analyzed by anunpaired t-test (significant difference: *). The difference between thedisease control group and the single drug-treated group was analyzed byDunnett-type multiple comparison test (significant difference: #). Thedifference between the combined treatment group and the singledrug-treated group was analyzed by Dunnett-type multiple comparison test(significant difference: ※). A value of p<0.05 was judged to be astatistically significant difference. Statistical analysis was conductedusing GraphPad Prism version 5.04 or 6.02. The results are shown inTables 1 to 5.

TABLE 1 Scopolamine-administered group Normal Disease Compound (I)Compound (I) control group control group 0.3 mg/kg 1 mg/kg 71.3 ± 3.154.4 ± 2.8* 58.7 ± 3.2 59.9 ± 3.4

TABLE 2 Scopolamine-administered group Normal Disease Compound (I)Compound (I) control group control group 3.3 mg/kg 10 mg/kg 73.8 ± 3.053.3 ± 2.2* 68.5 ± 2.0# 68.5 ± 1.6#

TABLE 3 Scopolamine-administered group Normal Disease Donepezil controlgroup control group 0.03 mg/kg 71.1 ± 3.3 55.0 ± 2.3* 62.7 ± 3.6

TABLE 4 Scopolamine-administered group Normal Disease DonepezilDonepezil control group control group 0.1 mg/kg 0.3 mg/kg 71.5 ± 4.853.9 ± 2.7* 66.2 ± 4.0 70.4 ± 4.8#

TABLE 5 Scopolamine-administered group Normal Disease Donepezil Compound(I) Donepezil 0.03 mg/kg and control group control group 0.03 mg/kg 1mg/kg Compound (I) 1 mg/kg 76.4 ± 2.3 54.8 ± 3.8* 57.8 ± 4.0 64.9 ± 2.273.1 ± 2.3 ※

Results

In T2, the rats of the disease control group exhibited a significantlylower percentage of exploration of the novel object than the rats of thenormal control group. This means that memory impairment was induced inthe rats by scopolamine.

Compound (I) exhibited a significant ameliorative effect on thepercentage of exploration of the novel object at 3.3 mg/kg (Table 2),but did not exhibit a significant effect at 1 mg/kg (Table 1). Donepezilhydrochloride exhibited a significant ameliorative effect on thepercentage of exploration of the novel object at 0.3 mg/kg (Table 4),but did not exhibit a significant effect at 0.03 mg/kg (Table 3). Whenthe effects of compound (I) and donepezil hydrochloride alone werecompared with the effect of their use in combination, in doses that areineffective with each alone, it was found that the combined treatmentgroup with compound (I) (1 mg/kg) and donepezil hydrochloride (0.03mg/kg) exhibited a significantly higher percentage of exploration of thenovel object than the donepezil hydrochloride (0.03 mg/kg) singledrug-treated group (Table 5). This result indicates an augmenting effecton cognitive function by compound (I) when in combination with donepezilhydrochloride.

1.-12. (canceled)
 13. A method for treating Alzheimer's disease,comprising administering(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof to a patient in needthereof.
 14. The method according to claim 13, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof, and the donepezil orpharmaceutically acceptable salt thereof are administered simultaneouslyor separately.
 15. The method according to claim 13, wherein thedonepezil or pharmaceutically acceptable salt thereof is donepezilhydrochloride.
 16. The method according to claim 13, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.
 17. The method according to claim 13, wherein the Alzheimer'sdisease is mild, moderate or severe Alzheimer's disease.
 18. A methodfor treating Lewy body dementia, comprising administering(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onerepresented by formula (I):

or a pharmaceutically acceptable salt thereof, and donepezil representedby formula (II):

or a pharmaceutically acceptable salt thereof to a patient in needthereof.
 19. The method according to claim 18, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof, and the donepezil orpharmaceutically acceptable salt thereof are administered simultaneouslyor separately.
 20. The method according to claim 18, wherein thedonepezil or pharmaceutically acceptable salt thereof is donepezilhydrochloride.
 21. The method according to claim 18, wherein the(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-oneor pharmaceutically acceptable salt thereof is(S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinoline-4(5H)-onemaleate.